Controlled release of a biologically active agents to a mucosal membrane improves therapeutic efficacy, safety, and patient compliance. Oral drug administration is associated with two phenomina, namely, 1) the first pass hepatic metabolism, and 2) systemic dilution. Mucosal drug delivery avoids the hepatic first pass metabolism and prevents systemic dilution of the drug, resulting in greater local bioavailability of a drug. Because mucosal drug delivery requires much lower amounts of the drug than oral administration, it minimizes the side effects of systemic drug circulation. Compared to oral drug administration, mucosal delivery also reduces the burden on the liver and other organs. Mucosal drug delivery can be used to provide therapeutic effectiveness proximal to the site of delivery, e.g. vaginal delivery of clotrimazole or miconazole nitrate for the treatment of vaginal yeast and fungal infections. However, delivery to a mucosal membrane also delivers drug to the systemic circulation, and can be used to make an active agent available for pharmacological effectiveness at another site or organ in the body. An example of such distal delivery is absorption of a cardiovascular drug through either a nasal or buccal mucosa.
Mucosal sites in the body include the cul-de-sac of the eye, buccal cavity, nose, rectum, vagina, periodontal pocket, intestines and colon. Due to natural eliminating or cleansing mechanisms of mucosal tissues, conventional dosage forms are not retained at the application site for any significant length of time. For example, drops of medications instilled in the cul-de-sac of the eye are easily eliminated; first, by overflowing, and subsequently, by drainage through puncta. Conventional vaginal dosage forms such as creams, ointments, suppositories, etc, are rapidly removed by self cleansing action of the vaginal tract.
For these and other reasons it is advantageous to have materials which exhibit adhesion to mucosal tissues, to administer one or more drugs or active agents over a period of time. Materials having controlled release capability are particularly desirable, and the use of sustained release mucoadhesives has received a significant degree of attention.
J. R. Robinson (U.S. Pat. No. 4,615,697) provides a good review of the various controlled release polymeric compositions used in mucosal drug delivery. The patent claims a controlled release treatment composition which includes a bioadhesive and an effective amount of a treating agent. The bioadhesive is a water swellable, but water insoluble fibrous, crosslinked, carboxy functional polymer containing (a) a plurality of repeating units of which at least about 80 percent contain at least one carboxyl functionality, and (b) about 0.05 to about 1.5 percent crosslinking agent substantially free from polyalkenyl polyether. While the polymers of Robinson are water swellable but insoluble, they are crosslinked, not thermoplastic, and are not as easy to formulate with active agents, and into the various dosage forms, as the copolymer systems of the present application.
Other approaches involving mucoadhesives which are the combination of hydrophilic and hydrophobic materials, are known. Orahesive.RTM. from E.R. Squibb & Co is an adhesive which is a combination of pectin, gelatin, and sodium carboxymethyl cellulose in a tacky hydrocarbon polymer, for adhering to the oral mucosa. However, such physical mixtures of hydrophilic and hydrophobic components eventually fall apart. In contrast, the hydrophilic and hydrophobic domains in the present invention produce an insoluble copolymer.
U.S. Pat. No. 4,948,580 describes a bioadhesive oral drug delivery system. The composition, includes a freeze-dried polymer mixture formed of the copolymer poly(methyl vinyl ether/maleic anhydride) and gelatin, dispersed in an ointment base, such as mineral oil containing dispersed polyethylene. U.S. Pat. No. 5,413,792 discloses paste-like preparations comprising (A) a paste-like base comprising a polyorganosiloxane and a water soluble polymeric material which are preferably present in a ratio by weight from 3:6 to 6:3, and (B) an active ingredient. U.S. Pat. No. 5,554,380 claims a solid or semisolid bioadherent orally ingestible drug delivery system containing a water-in-oil system having at least two phases. One phase comprises from about 25% to about 75% by volume of an internal hydrophilic phase and the other phase comprises from about 23% to about 75% by volume of an external hydrophobic phase, wherein the external hydrophobic phase is comprised of three components: (a) an emulsifier, (b) a glyceride ester, and (c)a wax material.
All the above compositions are physical mixtures, therefore they are more prone to break down and less likely to attain a long residence time. While their hydrophilic and hydrophobic components have some utility in drug delivery, using the hydrophilic and hydrophobic domains in the copolymers of the present invention make it is far easier to incorporate drugs within, and to formulate, dosage forms. Further, the compositions of the present invention do not break down upon hydration.